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Lecture 3
Autonomic nervous system
Sympathetic
Parasympathetic
Nerve impulses and synapses
Axon terminal
Synapse
Receptors on the effector organ
Basic arrangement of nerves:
CNS nerve ganglion nerve effector organ
Preganglionic and postganglionic nerves
▪ Preganglionic parasympathetic and preganglionic sympathetic
▪ Postganglionic para and postganglionic sympa
Preganglionic Postganglionic
Parasympa Acetylcholine (long) Acetylcholine (short)
Sympa Acetylcholine (short) Noradrenaline or dopamine (long)
Ganglionic receptor Effector receptor
Parasympa = Cholinoceptors or cholinergic receptors
Nicotinic receptor Muscarinic receptor
Sympa = Adrenoceptors oradrenergic receptors
Nicotinic receptor Muscarinic, Adrenaline, noradrenaline or dopamine receptors
5 key features of neurotransmitter function, which can be targets for pharmacotherapy
Synthesis
Storage
Release
Termination of action
Receptor effects
Acetylcholine (Ach) Produced in the nerve axon body and stored in the
axon terminal Synthesized from acetyl-CoA + choline (via enzyme
choline acetyltransferase or ChAT)▪ Acetyl CoA comes from the mitochondria (Krebs)▪ Choline is absorbed by the nerve cell from outside thru a
transporter called choline transporter (CHT)▪ Blocked by a research drug called Hemicholiniums
Once synthesized, Ach is transported to vesicles by a vessicle associated transporter (VAT)▪ Blocked by a research drug called vesamicol
Acetylcholine (Ach)
Release of neurotransmitter is dependent on calcium entry into the nerve axon
▪ Once an action potential (nerve impulse) reaches the terminal end of the axon, calcium channels open.
▪ This promotes vesicles to merge with the axonal membrane to release contents into the synapse
▪ Release can be blocked by botolinum toxin
Acetylcholine (Ach)
Once released, Ach binds with cholinoceptors on the effector organ = effect
Ach is then deactivated by AChe(acetylcholinesterase)
▪ Very rapidly
▪ Split into acetate and choline▪ Choline is then recycled back into the nerve axon
Noradrenaline or Norepinephrine
Synthesis
▪ Starts as a tyrosine molecule, eventually modified into dopa dopamine norepinephrine epinephrine▪ Conversion of tyr to dopa inhibited by drug metyrosine
Storage
▪ Stored in vesicles via transporter VMAT (vesicular monoamine transporter)▪ Blocked by drug reserpine = depletion of adrenergic stores
Noradrenaline or Norepinephrine Release▪ Similar to cholinergic release = nerve impulse stimulates
opening of Ca++ channels
Termination of action▪ 2 processes:▪ Simple diffusion away from the receptor site (with eventual
metabolism in the plasma or liver)
▪ Reuptake into the nerve terminal by NET (norepinephrine transporter)
Blocked by drugs such as cocaine and tricyclic antidepressants (TCAs) = increased neurotransmitter activity in the synapse
NANC or nanadrenergic, noncholinergicneurons
Some parts of the ANS does not follow the usual classification
May use a combination of adrenergic and cholinergic receptors and transmitters
May use other substances (ex. nitric oxide, cholecystokinin, enkephalins, serotonin, somatostatin, etc.)
ANS = sympa and parasympa
Multifactorial and multilevel interactions
Ex. blood pressure or mean arterial pressure (MAP)
▪ MAP = CO x TPR▪ CO = SV x HR
SV = Venous return = blood volume = affected by oral intake and kidneys
▪ TPR = arterial diameters
▪ Give norepinephrine (a potent vasoconstrictor) in small doses = promote vasoconstriction and slightly increased HR increase BP▪ But the TPR will induce the parasympa to HR (via vagus nerve
and baroreceptors in the carotid body)
▪ Therefore = there will be an BP with a corresponding HR, despite the direct action of NE to the heart
Historically, plant derivatives, muscarine(mushroom Amanita muscaria) and nicotine (tobacco), were applied or ingested, which produced parasympathetic effects. Receptors were termed muscarinic or nicotinic
Usually has a diffuse action (due to wide spread presence of cholinergic receptors) Selectivity of action may be achieved via:▪ Modifying the drug for specific receptors
▪ Modifying route of administration = ex. eye drops
Muscarinic Nicotinic
Type of receptor G protein-linked (stimulates 2nd
messenger system)
Ion channel
Location Nerves, CNS, heart, smooth muscle, glands
Skeletal muscle (NMJ), CNSPreganglionic nerves
Receptor Type Location
M1 Nerves
M2 (Cardiac M2) Heart, nerves, smooth muscle
M3 Glands, smooth muscle, endothelium
M4 CNS
M5 CNS
NM Skeletal muscle (NMJ)
NN CNS, postganglionic cell body, dendrites
Direct acting agents bind to and activate muscarinic or nicotinic receptors
Acetylcholine, methacholine, carbachol, bethanechol
Indirect acting agents inhibit acetylcholinesterase
Neostigmine, carbaryl, physostigmine, edrophonium
Pharmacokinetics
Permanently charged = hydrophilic
▪ Poorly absorbed into the CNS
Rapidly metabolized by Ach-ase (AChe)
▪ Ach = very rapidly metabolized▪ Need to give a very large amount and injected very quickly to
produce an effect
▪ Modified drugs are more resistant to Ach-asemetabolism, and therefore longer duration of action▪ Methacholine < Carbachol < Bethanechol
Pharmacodynamics MOA:
▪ activates muscarinic receptors on effector organ
▪ Inhibits release of neurotransmitters on nerve terminals with muscarinic receptors
▪ In effect, promote parasympa activity and inhibit sympaactivity
▪ Muscarinic receptors activate the 2nd messenger cascade (ex. IP3 and DAG cascade)
▪ Nicotinic receptors opens up Na+ and K+ channels causing depolarization of the nerve cell or NMJ, producing contraction of the muscle
Pharmacodynamics▪ Special activity at nicotinic receptors during prolonged
exposure to agonists▪ Prolonged agonist occupancy of the nicotinic receptor will
eventually stop its activity (ex. the muscle initially contracts then relaxes despite exposure to the agonist)
▪ Continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane = “depolarizing blockade” (receptor becomes insensitive to more agonist concentrations)
▪ Receptor eventually becomes desensitized to agonist and is becomes more difficult to be reversed (useful in muscle relaxant drugs = ex. succinylcholine)
Choline Ester Susceptibility to cholinesterase
Muscarinicaction
Nicotinicaction
Acetylcholinechloride
++++ +++ +++
Methacholine + ++++ None
Carbachol Negligible ++ +++
Bethanechol Negligible ++ None
Organ System Effects
Eye
▪ Pupillary constriction and accomodation
Cardiovascular system
▪ Reduction in peripheral vascular resistance
▪ Decreased HR
Respiratory system
▪ Bronchoconstriction and increased glandular activity
Organ System Effects
Gastrointestinal
▪ Increase secretory and motor activity of the gut
Genitourinary
▪ Promote voiding
Secretory glands
▪ Stimulate sweat, lacrimal, nasopharyngeal glands
Organ System Effects Central Nervous System▪ Muscarinic receptors = ▪ role in cognition, learning
▪ hunger
▪ Nicotinic receptors = ▪ release of other transmitters (ex. glumatate, serotonin, GABA,
etc)
▪ Chronic exposure can lead to desensitization and greater release of dopamine in the mesolimbic system
Contributes to the mild alerting and addictive qualities of cigarette smoking
Organ Response Organ Response
EyeIris muscle (pupils) Contraction (miosis)
LungsBronchial muscle constriction
Ciliary muscle Accomodation (near vision)
Bronchial glands stimulation
Heart GI Tract
SA node rate (chrontropy) Motility Increase
Atria inotropy Sphincters Relax
AV node conduction velocity (dromotropy)
Secretion Stimulation
Ventricles Mildinotropy Urinary bladder
Blood vessels Dilation (EDRF)Constriciton (at very high doses)
Detrusor muscleTrigone &
sphincter
Contract
Relax
Salivary glands Stimulate Sweat glands Stimulate
Act by inhibiting acetylcholinesterase = increasing or prolonging Ach activity on the synapse
3 groups Alcohols with quaternary ammonium group
▪ Edrophonium
Carbamic acid esters with quaternary or tertiary ammonium groups▪ Carbamates (Ex. neostigmine, pyridostigmine, physostigmine)
Organic derivatives of phosphoric acid▪ Organophosphates (ex. echothiophate) and thiophosphates
(malathion)
Pharmacokinetics
Carbamates
▪ Generally hydrophilic, and therefore poor absorption in lungs and gut and skin
Organophosphates
▪ Generally hydrophilic, but more lipid soluble than carbamates = better absorbed in skin, gut and lungs▪ Potentially more dangerous to humans, but can kill more insects
▪ Relatively shorter half-life in the environment than carbamates
Pharmacokinetics
Thiophosphates
▪ More lipid soluble = better drug absorption
▪ Must be activated in the body to produce an effect
▪ Easily metabolized into inactive products among birds and mammals, but not in insects and fishes▪ Makes it potentially more safe to humans.
Pharmacodynamics MOA: Inhibits Ach-ase
Alcohols▪ Reversibly bind with Ach-ase, preventing binding with Ach.
▪ Effect is of short duration (5-15min)
Carbamates▪ Covalently bonds with Ach-ase. = longer duration (30min-
6hours)
Organophosphates▪ Phosphorylates with Ach-ase = extremely stable bond =
(duration, ≥100hours)
Uses Approximate duration of action
AlcoholsEdrophonium
Myasthenia gravis, ileus, arrythmias
1-15min
Carbamates
Neostigmine Myasthenia gravis 0.5-2 hours
Pyridostigmine MG 3-6 hours
Physostigmine Glaucoma 0.5-2 hours
OrganophosphatesEchothiophate Glaucoma 100 hours
Organ System Effects CNS
▪ Produce mild alertness
Eye, respiratory tract, GIT, urinary▪ Similar to cholinergic drug effects
Cardiovascular system▪ Can increase activity on both para and sympa ganglia▪ Heart = negative chronotropic, dromotropic and inotropic effects
▪ Blood vessels lack cholinergic innervation. sympathetic response vascular constriction increase in blood pressure
▪ NET effect = HR, CO, TPR = BP
▪ At toxic doses, there will be severe bradycardia = hypotension
Organ System Effects
Neuromuscular Junction (NMJ)
▪ At low doses = intensify action of Ach at the NMJ = increase muscular contractions. May help treat muscle weakness in myasthenia gravis
▪ Moderate doses = may produce fasciculations of the muscle unit (ex. tonic-like seizure)
▪ High doses = prolonged relaxation (neuromuscular depolarizing blockade, as in succinylcholine)
Treatment for
Diseases of the eye (Glaucoma)
Gastrointestinal and urinary tract (motility problems, postoperative atony, neurogenic bladder)
Neuromuscular junction (myasthenia gravis)
Alzheimer’s disease
Excess of parasympathetic effects Nausea, vomiting, diarrhea, urinary urgency, salivation,
cutaneous vasodilation, bronchial constriction, seizures, coma, death
Nicotine overdose Fatal dose is 40mg, or 1 drop of the pure liquid (in essence
is the amount in 2 cigarettes)▪ Destroyed by heat, and exhaled
Chronic smoking = behavioral therapy, nicotine patch, nasal spray or inhaler▪ New drug Varenicline = prevents release of dopamine in the
thalamus = reduce the rewarding/addicting sensation▪ Side effects = nausea, insomnia, anxiety, depression, suicidal
ideation
Pesticide/Insecticide overdose (organophosphates)
“Muscarinic excess” = miosis, salivation, sweating, bronchial constriction, vomiting, diarrhea, convulsions, coma, muscle and respiratory depression
Treatment = atropine
Used during warfare = “nerve gas”
Also called parasympatholytic Cholinoceptor antagonists Nicotinic antagonists
▪ Ganglion blockers = little clinical significance (because of its very broad effects)
▪ NMJ blockers = muscle relaxants
Muscarinic antagonists▪ Atropine = basic drug▪ Synthetic drugs = developed for more specific and less toxic
effects▪ Tertiary = 3rd generation (pirenzepine, dicyclomine, trpicamide,
benztropine)▪ Quaternary = 4th generation (propantheline, glycopyrrolate,
tiotropium)
Atropine Found from the plant Atropa belladona (“deadly
nightshade”)
Generally well absorbed▪ Tertiary drugs enter the CNS readily (more lipid soluble)
▪ Quaternary drugs less lipid soluble (less absorbed in the GUT and CNS) = more peripheral activity
Elimination: 2 phases▪ Rapid phase = t½ 2 hours
▪ Slow phase = t½ 13 hours
▪ Excreted mainly in the urine
Atropine
MOA = reversible blockade of cholinomimeticactions at muscarinic receptors (may be overcome by large doses of Ach)
Inverse agonists = stop the muscarinic receptor from being active
Organ System Effects
CNS
▪ Mild CNS effect
▪ Treatment for tremors in Parkinson’s disease▪ Due to relative excess of cholinergic activity (due to decreased
dopamine activity in the brain)
Eye
▪ Used by ophthalmologists to examine the eye
▪ Mydriasis (pupil dilation)
Organ System Effects
Cardiovascular
▪ Stimulates SA node = tachycardia
▪ Shortens AV node conduction = tachycardia
▪ Blood vessels have minimal innervations from parasympa = mild effect on BP
▪ NET effect = HR but normal BP
Respiratory
▪ Mild bronchodilation and reduce bronchial secretions▪ Useful during inhalational anesthetics
Organ System Effects
Gastrointestinal
▪ Decrease salivary, stomach and intestinal secretions
▪ Decreased peristalsis = prolonged GI time
Genitourinary
▪ Relaxes urinary bladder = slows voiding
Sweat glands
▪ Decreases sweating = may affect temperature regulation, called atropine fever
Parkinson’s disease (in combination with dopamine drugs)
Motion sickness Due to cholinergic activation of vestibular nerves (ear) Scopolamine best used to treat motion sickness
For eye exam Preparation for pre-operative patients who will
need inhalational anesthetics Asthma Ipratropium = bronchodilation and decreased
secretions
Reversing bradycardia
Acute myocardial infarction and resuscitation
Gastrointestinal
Peptic ulcer disease, diarrhea
Antidote for nerve gas and organophosphate poisoning and some types of mushroom poisoning
Hyperhydrosis (excessive sweating)
Symptoms: dry mouth, mydriasis, tachycardia, hot and flushed skin, agitation and delirium
“dry as a bone, blind as a bat, red as a beet, mad as a hatter”